This invention relates to novel bicyclic-substituted pyridopyrimidine derivatives. These derivatives are useful in the treatment of abnormal cell growth, such as cancers, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
It is known that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e., a gene which, on activation, leads to the formation of malignant tumor cells). Many oncogenes encode proteins that are aberrant tyrosine kinases capable of causing cell transformation. Alternatively, the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
Receptor tyrosine kinases are enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intracellular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. The erbB-2 protein, e.g. c-erbB-2, is a receptor tyrosine kinase which is homologous to the epidermal growth factor (EGF) receptor. Other receptor tyrosine kinases include c-met, tie-2, PDGFr, FGFr, and VEGFR. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer. It has also been shown that epidermal growth factor receptor (EGFR), which possesses tyrosine kinase activity, is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors. In particular, clinical and experimental evidence suggests a role for overexpression of the erbB-2 protein in the progression of human breast, ovarian and non-small lung carcinomas. For example, amplification and/or overexpression of the erbB-2 gene have been shown in adenocarcinomas of the breast, ovary, lung and stomach. In breast carcinoma, a correlation has been observed between gene amplification and overexpression of erbB-2 protein and the aggressiveness of the malignancy (Slamon et al, Science, (1987), 237, 177-182; Slamon et al, Science, (1989), 244, 707-712). The overexpression of erbB-2 has also been directly linked to the malignant conversion of cancer cells. Inhibition of the erbB2 receptor by monoclonal antibodies have been found to inhibit the proliferation of a human breast carcinoma cell line in human tissue culture (Hudziak et al, Mol. Cell. Biol., (1989), 9, 1165-1172), and an antibody directed to the rat erbB-2 protein, has been reported to inhibit the tumorigenicity of fibroblasts transformed by the mutant rat erbB-2 oncogene (Drebin et al, Proc. Nat'l. Acad. Sci., (1986), 83, 9126-9133; Drebin etal, Oncogene, (1988), 2, 387-399).
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as selective inhibitors of the growth of mammalian cancer cells. For example, erbstatin, a tyrosine kinase inhibitor, selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor. Thus, the compounds of the present invention, which are selective inhibitors of erbB-2 receptor tyrosine kinases, are useful in the treatment of abnormal cell growth, in particular cancer, in mammals.
Compounds which are ErbB2 receptor inhibitors include GW-282974 (Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of The Woodlands, Tex. USA) and 2B-1 (Chiron), for example those indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), which are all hereby incorporated herein in their entireties by reference. ErbB2 receptor inhibitors useful in the present invention are also described in U.S. application Ser. No. 09/488,350 (filed Jan. 20, 2000), and in U.S. application Ser. No. 09/488,378 (filed Jan. 20, 2000), both of which are incorporated in their entireties herein by reference.
Other compounds that are useful in the treatment of hyperproliferative diseases are also disclosed in the following co-pending patent applications: PCT international patent application WO 97/49688 (published Dec. 31, 1997), U.S. patent application Ser. No. 09/308,602 (filed Nov. 5, 1997), U.S. patent application Ser. No. 08/953,078 (filed Oct. 17, 1997), U.S. patent application Ser. No. 08/653,786 (filed May 28, 1996), PCT international patent application publication number WO 96/40142 (published Dec. 19, 1996), PCT international patent application publication number WO 97/13771 (published Apr. 17, 1997), and PCT international patent application publication number WO 95/23141 (published Aug. 31, 1995). Each of the foregoing United States and PCT international patent applications is incorporated herein by reference in its entirety.